Evaluation of Machine Learning/Molecular Mechanics End-State Corrections with Mechanical Embedding to Calculate Relative Protein-Ligand Binding Free Energies.

The development of machine-learning (ML) potentials offers significant accuracy improvements compared to molecular mechanics (MM) because of the inclusion of quantum-mechanical effects in molecular interactions. However, ML simulations are several times more computationally demanding than MM simulations, so there is a trade-off between speed and accuracy. One possible compromise are hybrid machine learning/molecular mechanics (ML/MM) approaches with mechanical embedding that treat the intramolecular interactions of the ligand at the ML level and the protein-ligand interactions at the MM level.

Understanding the Catalytic Efficiency of Two Polyester Degrading Enzymes: An Experimental and Theoretical Investigation.

The discovery of novel plastic degrading enzymes commonly relies on comparing features of the primary sequence to those of known plastic degrading enzymes. However, this approach cannot always guarantee success. This is exemplified by the different degradation rates of the two polymers poly(ethylene terephthalate) (PET) and polybutylene succinate (PBS) by two hydrolases: PETase from and Cut from .

A molecular mechanism to diversify Ca signaling downstream of Gs protein-coupled receptors.

A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cβ (PLCβ) isozymes to increase cytosolic Ca in living cells is exclusive to Gq- and Gi-sensitive G protein-coupled receptors (GPCRs). Here we extend this central tenet and show that Gs-GPCRs also partake in inositol-lipid signaling and thereby increase cytosolic Ca. By combining CRISPR/Cas9 genome editing to delete Gα, the adenylyl cyclase isoforms 3 and 6, or the PLCβ1-4 isozymes, with pharmacological and genetic inhibition of Gq and G11, we pin down Gs-derived Gβγ as driver of a PLCβ2/3-mediated cytosolic Ca release module.

Biosynthesis of the corallorazines, a widespread class of antibiotic cyclic lipodipeptides.

Corallorazines are cyclic lipodipeptide natural products produced by the myxobacterium B035. To decipher the basis of corallorazine biosynthesis, the corallorazine nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster was identified and analyzed in detail. Here, we present a model of corallorazine biosynthesis, supported by bioinformatic analyses and investigations on the bimodular NRPS synthesizing the corallorazine core.

Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy.

The cyclodepsipeptide FR900359 (FR) and its analogs are able to selectively inhibit the class of G proteins by blocking GDP/GTP exchange. The inhibitor binding site of G has been characterized by X-ray crystallography, and various binding and functional studies have determined binding kinetics and mode of inhibition. Here we investigate isotope-labeled FR bound to the membrane-anchored G protein heterotrimer by solid-state nuclear magnetic resonance (ssNMR) and in solution by liquid-state NMR.